Self-injurious behavior (SIB) is a significant problem for many individuals with mental retardation. As yet, the mechanisms that underlie self-injury are unknown, and definitive treatments remain elusive. In this project we will use pemoline and GBR12909-induced self-biting in the rat to establish the relationship between changes in neostriatal neurotransmitter release and self-biting behavior, and also to determine the critical role of the neostriatum for the initiation and/or maintenance of SIB. The first aim is approached by dose-response studies which determine the relationship between neostriatal pemoline levels, patterns of neurotransmitter release, and behavioral responses. Pharmacologic manipulations will follow, to establish the primacy of the timing and/or the quantity of neurotransmitter(s) released, on the subsequent expression of SIB. These studies will also determine if the above relationships are developmentally-dependant. In concurrent aims, the proposed studies will establish the specificity of the neostriatum in mediating pemoline-induced behaviors. The effects of focal neostriatal and cortical lesions, and cellular alterations in the response to dopamine (DA) in neostriatal slices will be explored in detail. Based upon preliminary data, our working hypothesis is that the cascade of events which leads to SIB originates with pemoline-induced dopamine release, initially sensitizing neostriatal neurons through glutamate dependant mechanisms, and later initiating though perhaps not maintaining SIB through neostriatal DA overflow. We also predict that we will be able to effectively antagonize SIB in this animal model. Insights from this model of SIB will significantly advance our understanding of both the pathophysiology and ultimate pharmacotherapy of self-injury in mental retardation.